title: Gene expression profiling analysis reveals arsenic-induced cell cycle arrest and apoptosis in p53-proficient and p53-deficient cells through differential gene pathways.
abstract: Arsenic (As) is a well-known environmental toxicant and carcinogen as well as an effective chemotherapeutic agent. The underlying mechanism of this dual capability, however, is not fully understood. Tumor suppressor gene p53, a pivotal cell cycle checkpoint signaling protein, has been hypothesized to play a possible role in mediating As-induced toxicity and therapeutic efficiency. In this study, we found that arsenite (As(3+)) induced apoptosis and cell cycle arrest in a dose-dependent manner in both p53(+/+) and p53(-/-) mouse embryonic fibroblasts (MEFs). There was, however, a distinction between genotypes in the apoptotic response, with a more prominent induction of caspase-3 in the p53(-/-) cells than in the p53(+/+) cells. To examine this difference further, a systems-based genomic analysis was conducted comparing the critical molecular mechanisms between the p53 genotypes in response to As(3+). A significant alteration in the Nrf2-mediated oxidative stress response pathway was found in both genotypes. In p53(+/+) MEFs, As(3+) induced p53-dependent gene expression alterations in DNA damage and cell cycle regulation genes. However, in the p53(-/-) MEFs, As(3+) induced a significant up-regulation of pro-apoptotic genes (Noxa) and down-regulation of genes in immune modulation. Our findings demonstrate that As-induced cell death occurs through a p53-independent pathway in p53 deficient cells while apoptosis induction occurs through p53-dependent pathway in normal tissue. This difference in the mechanism of apoptotic responses between the genotypes provides important information regarding the apparent dichotomy of arsenic's dual mechanisms, and potentially leads to further advancement of its utility as a chemotherapeutic agent.
authors.affiliation: Institute for Risk Analysis and Risk Communication, Department of Environmental and Occupational Health Sciences, University of Washington, Seattle, WA 98105, USA. yuxz@u.washington.edu
authors.forename: Xiaozhong
authors.initials: X
authors.lastname: Yu
authors.forename: Joshua F
authors.initials: JF
authors.lastname: Robinson
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Gribble
authors.forename: Sung Woo
authors.initials: SW
authors.lastname: Hong
authors.forename: Jaspreet S
authors.initials: JS
authors.lastname: Sidhu
authors.forename: Elaine M
authors.initials: EM
authors.lastname: Faustman
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects* / Q000235:genetics; D018053:Arsenites / Q000633:toxicity*; D002453:Cell Cycle / Q000187:drug effects* / Q000235:genetics; D002478:Cells, Cultured; D004249:DNA Damage; D004785:Environmental Pollutants / Q000633:toxicity*; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D015870:Gene Expression / Q000187:drug effects*; D020869:Gene Expression Profiling; D051379:Mice; D051267:NF-E2-Related Factor 2 / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016159:Tumor Suppressor Protein p53 / Q000172:deficiency* / Q000235:genetics
chemical_list: D018053:Arsenites; D004785:Environmental Pollutants; D051267:NF-E2-Related Factor 2; D016159:Tumor Suppressor Protein p53; C015001:arsenite